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FOR IMMEDIATE RELEASE | Thu Aug 30 16:42:03 EDT 2007

Revealing estrogen’s secret role in obesity

BOSTON, Aug. 20, 2007 — New research on the effects of the female sex hormone estrogen in the brain lend credence to what many women have suspected about the hormonal changes that accompany aging: Menopause can make you fat.

Scientists long have sought to understand how changes in hormones during menopause could account for the increase in appetite and accompanying weight gain that often occurs among aging women.

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In a series of animal experiments described today at the 234th national meeting of the American Chemical Society, the world’s largest scientific society, researchers showed how estrogen receptors located in the hypothalamus serve as a master switch to control food intake, energy expenditure and body fat distribution. When these receptors are destroyed, the animals immediately begin to eat more food, burn less energy and pack on pounds.

This research seems to support a link between estrogen and regulation of obesity, especially the dangerous accumulation of abdominal fat linked to heart disease, diabetes, and cancer, says Deborah J. Clegg, Ph. D., assistant professor of psychiatry at the University of Cincinnati Medical Center, who is directing the studies.

The findings may also help scientists develop more targeted hormone replacement therapies, capable of stimulating estrogen receptors in one part of the brain or body while dampening it in the next, Clegg says.

Estrogen receptors are located on cells throughout a woman’s body. Previous studies have shown that one type of estrogen receptor, known as estrogen receptor alpha or ER-alpha, plays a role in regulating food intake and energy expenditure. But scientists have been unable to pinpoint exactly where these fat-regulating receptors reside or how they work to govern these behaviors.

To determine the effect of dwindling estrogen levels in the brain, Clegg and her colleagues are focusing on two ER-alpha rich regions located in the hypothalamus, an area of the brain that controls body temperature, hunger and thirst. The first region, called the ventromedial nucleus or VMN, is a key center for energy regulation.

Using a relatively new gene-silencing technique called RNA interference, the researchers in earlier research deactivated the alpha-receptors in the VMN. The estrogen receptors in other regions of the brain maintained their normal capacity.

When estrogen levels in the VMN dipped, the animals’ metabolic rate and energy levels also plummeted. The findings show the animals quickly developed an impaired tolerance to glucose and a sizable weight gain, even when their caloric intake remained the same. What’s more, the excess weight went straight to their middle sections, creating an increase in visceral fat.

The findings suggested that the ER-alpha in this region plays an essential role in controlling energy balance, body fat distribution and normal body weight.

Clegg now plans to perform a similar experiment to deactivate ER-alpha in the arcuate nucleus region of the hypothalamus. This region contains two populations of neurons: one puts the brake on food intake and the other stimulates food intake. Clegg anticipates that a loss of estrogen in this region may create an increase in the animals’ appetites as well as their weight.

Clegg says her studies address an area that is sorely needed given the incidence and impact of gender differences in obesity and its complications.

“The accumulation of abdominal fat puts both men and women at a heightened risk of cardiovascular disease, diabetes, and insulin resistance,” she says. “Women are protected from these negative consequences as long as they carry their weight in their hips and saddlebags. But when they go through menopause and the body fat shifts to the abdomen, they have to start battling all of these medical complications.”

By identifying the critical brain regions that determine where body fat is distributed, Clegg says her findings may help scientists design hormone replacement therapies to better manage and manipulate estrogen levels.

“If we could target those critical regions and estrogen receptors associated with weight gain and energy expenditure, we could perhaps design therapies that help women sidestep many of the complications brought on by the onset of menopause,” she says.

— Susan Gaidos

All papers are embargoed until date and time of presentation unless otherwise noted

Abstract

Obesity and its associated health disorders and costs are increasing. Fat distribution and the associated risk for developing cardiovascular problems, type-2 diabetes mellitus, certain cancers and other disorders differ for men and women. Men and post-menopausal women have greater risk of developing complications of obesity than younger women. The ventromedial hypothalamus (VMH) is an important regulator of energy homeostasis, and two of its sub-areas, the ventrolateral portion (VL VMN) and the arcuate (ARC) respond to hormones and other signals to control energy intake and expenditure. When large VMH lesions are made that include both the VL VMN and the ARC, animals, especially females, eat more food, burn less energy and become obese. Both the ARC and the VMN contain dense estrogen receptors (specifically estrogen receptor alpha, ERÁ), and we have data that suggests reducing estrogen causes obesity, and estrogen mediates the sensitivity of the brain to leptin, we also report that when the VMH ERÁ are decreased following injections of an adeno-associated virus, the reduction of estrogen signaling and consequent reduction in leptin signaling are what results in increased body weight. Our observations have determined the relative contribution of estrogen signaling through ERÁ in the regulation of food intake and body weight in the VMN. Our findings have direct relevance in increasing our understanding of the mechanisms by which estrogen regulates body weight, and this will assist in determining potential therapeutic agents for menopausal women to decrease adiposity and the propensity of diseases associated with obesity.

Researcher Provided Non-Technical Summary

Briefly explain in lay language what you have done, why it is significant and what are its implications (particularly to the general public).

We have been focusing on the role of estrogen in regulating food intake, body weight, energy expenditure, and body fat distribution. It is known that when women go through menopause, there are dramatic changes that occur with respect metabolism. After menopause, there is a reduction in energy expenditure, which makes it harder to maintain body weight, there is an increase in fat mass, specifically an increase in fat mass in the abdominal or visceral region. We know that fat accumulation in that region of the body is associated with diseases such as diabetes, cancer, and heart disease. Therefore, we are trying to discover which are the critical estrogen receptors that are responsible for some of these metabolic effects so that we can target 'designer' estrogen therapies to hit only those receptors to protect women from complications of metabolic diseases after they go through menopause.

How new is this work and how does it differ from that of others who may be doing similar research?

To our knowledge, the role of estrogen receptors regulating these metabolic processes has been relatively ignored. We believe that we will be the first to demonstrate that estrogen in the brain regulates where fat is distributed.

Special Instructions/feedback:

The data we will be presenting are exciting, and very easy for the public to understand - they have huge potential health benefits. We discuss some of the problems with the previous research trials on hormone replacement therapy.